Neurochemical and electrophysiological studies have demonstrated that glycine modulates excitatory neurotransmission in the central nervous system. These actions are mediated through strychnine-insensitive glycine receptors with markedly different structural requirements for ligand binding and regional distribution than strychnine-sensitive sites associated with the role of glycine as an inhibitory neurotransmitter.
Neurotransmissions mediated through the N-methyl-D-aspartate (NMDA) receptor supramolecular complex are believed to be associated with numerous pathologic and physiologic mechanisms which include: kindling development, ischemic neuronal injury, synaptogenesis, spatial learning and long-term potentiation. Regulation of these neuronal mechanisms by NMDA-mediated processes is believed to involve activation of a receptor-gated ion channel.
Evidence now available clearly indicates that the NMDA complex is regulated, at least in part, by the amino acid glycine. Glycine has been shown to increase NMDA evoked currents in various tissues by increasing the opening frequency of the NMDA channel. Thus, NMDA-induced influx and intracellular accumulation of calcium are stimulated by glycine, which interacts with its own distinct site on the receptor. It is believed that the accumulation of intracellular calcium is implicated in the various neuropathologies.
Up to the present time, all drugs, including felbamate, used in the treatment of neuropsychopharmacological disorders and neurodegenerative diseases function as prophylactics against the symptoms of these disorders and diseases as opposed to being curatives.
In accordance with the present invention, it has been established that felbamate interacts with strychnine-insensitive glycine receptors and that felbamate's neuroprotective effects are at least in part mediated through a strychnine-insensitive glycine receptor mechanism.
Felbamate is a well known pharmaceutical compound having been described together with methods for its manufacture and use in U.S. Pat. Nos. 2,884,444; 4,868,327; 4,978,680; 5,055,489; 5,072,056 and 5,082,861.
One of the objects of the present invention is to provide methods and compositions for the treatment and control of the symptoms of neuropsychopharmacological disorders and neurodegenerative diseases.
Another object of the present invention to provide methods and compositions for the treatment and control of the symptoms of neuropsychopharmacological disorders and neurodegenerative diseases resulting from excessive activation of the NMDA through the use of felbamate.
Accordingly, it has been found that felbamate chemically described as 2-phenyl-1,3-propanediol dicarbamate is a compound which has demonstrated superior properties with respect to the treatment of disorders such as hypoxia, either alone, e.g. CO poisoning, near drowning; or combined with ischemic blood flow reduction, e.g. cardiac arrest, stroke; anxiety and neurodegenerative diseases, e.g. Guam ALS, Parkinson's disease, alzheimer's disease, dementia and lathyrism.